key: cord-1002679-4uzjqfjz
authors: Lokken, Erica M.; Walker, Christie L.; Delaney, Shani; Kachikis, Alisa; Kretzer, Nicole M.; Erickson, Anne; Resnick, Rebecca; Vanderhoeven, Jeroen; Hwang, Joseph K.; Barnhart, Nena; Rah, Jasmine; Mccartney, Stephen A.; Ma, Kimberly K.; Huebner, Emily M.; Thomas, Chad; Sheng, Jessica S.; Paek, Bettina W.; Retzlaff, Kristin; Kline, Carolyn R.; Munson, Jeff; Blain, Michela; Lacourse, Sylvia M.; Deutsch, Gail; Adams Waldorf, Kristina
title: Clinical Characteristics of 46 Pregnant Women with a SARS-CoV-2 Infection in Washington State
date: 2020-05-19
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2020.05.031
sha: 0ad11c8de3536bfb54f1201d5829fe78700bd72d
doc_id: 1002679
cord_uid: 4uzjqfjz

Abstract Background The impact of the coronavirus disease 2019 (Covid-19) on pregnant women is incompletely understood, but early data from case series suggest a variable course of illness from asymptomatic or mild disease to maternal death. It is unclear whether pregnant women manifest enhanced disease similar to influenza viral infection or whether specific risk factors might predispose to severe disease. Objective To describe maternal disease and obstetrical outcomes associated with Covid-19 disease in pregnancy to rapidly inform clinical care. Study Design Retrospective study of pregnant patients with a laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection from six hospital systems in Washington State between January 21, 2020 and April 17, 2020. Demographics, medical and obstetric history, and Covid-19 encounter data were abstracted from medical records. Results A total of 46 pregnant patients with a SARS-CoV-2 infection were identified from hospital systems capturing 40% of births in Washington State. Nearly all pregnant individuals with a SARS-CoV-2 infection were symptomatic (93.5%, n=43) and the majority were in their second or third trimester (43.5%, n=20 and 50.0%, n=23, respectively). Symptoms resolved in a median of 24 days (interquartile range 13-37). Seven women were hospitalized (16%) including one admitted to the intensive care unit. Six cases (15%) were categorized as severe Covid-19 disease with nearly all patients being either overweight or obese prior to pregnancy, asthma or other co-morbidities. Eight deliveries occurred during the study period, including a preterm birth at 33 weeks to improve pulmonary status in a woman with Class III obesity. One stillbirth occurred of unknown etiology. Conclusions Nearly 15% of pregnant patients developed severe Covid-19, which occurred primarily in overweight or obese women with underlying conditions. Obesity and Covid-19 may synergistically increase risk for a medically-indicated preterm birth to improve maternal pulmonary status in late pregnancy. Collectively, these findings support categorizing pregnant patients as a higher risk group, particularly for those with chronic co-morbidities.

to improve pulmonary status in a woman with Class III obesity. One stillbirth occurred of 125 unknown etiology. 126

Conclusions: Nearly 15% of pregnant patients developed severe Covid-19, which 127 occurred primarily in overweight or obese women with underlying conditions. Obesity 128 and Covid-19 may synergistically increase risk for a medically-indicated preterm birth to 129 improve maternal pulmonary status in late pregnancy. Collectively, these findings 130 support categorizing pregnant patients as a higher risk group, particularly for those with 131 chronic co-morbidities. 132

The coronavirus disease of 2019 has led to the largest and deadliest 134 pandemic since the 1918 influenza pandemic. The first reported case of Covid-19 in the 135 United States was in Washington State on January 21, 2020; the United States now has 136 the highest rates of Covid-19 prevalence and mortality worldwide(1, 2). Covid-19 is 137 caused by the severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-138

2), which results in a spectrum of disease ranging from asymptomatic and mild cases to 139 respiratory failure, shock, multiorgan dysfunction and death (3). 140

The clinical course of Covid-19 in pregnant women is incompletely understood and 142 there is concern for enhanced disease in some pregnant women and an increased risk 143 for spontaneous abortion, preterm birth or morbidity/mortality in the fetus and 144 neonate(4-8). Several case series have reported a variable course of illness in the 145 antepartum, intrapartum, and postpartum periods (9) (10) (11) (12) (13) (14) . Limited reports suggesting 146 vertical transmission underscore the potential vulnerability of the fetus and neonate (15-147 18) . Further, the relationship between timing of infection in pregnancy and the long-term 148 impacts on neurodevelopmental and neuropsychiatric outcomes in the children are 149 unknown (19, 20) . Many questions remain unanswered, including whether pregnancy is 150 a high-risk state for enhanced disease in some circumstances and the impact of 151 infection on the developing fetus and neonate. 152 9 Emergency (22) . In response to the pandemic, the Washington State Covid-19 in 156

Pregnancy Collaborative was established to investigate cases among pregnant patients 157 at major tertiary referral centers and community hospitals disproportionately impacted 158 by the pandemic. The study objective was to describe maternal and obstetrical 159 outcomes associated with Covid-19 disease in pregnancy to rapidly inform clinical care. 

We identified pregnant women (>18 years) with laboratory-confirmed SARS-CoV-2 165 infections from six hospital systems in Washington State between January 21, 2020 and 166

April 17, 2020. All pregnant patients with a positive SARS-CoV-2 test result during any 167 trimester of pregnancy, regardless of symptoms, were included. All testing was 168 performed using a polymerase chain reaction (PCR) test, which varied in assay design 169 and source by institution. Participating 

We used criteria for Covid-19 disease severity previously defined in non-pregnant 202 adults(24) and subsequently applied to pregnant women(25). Categories were defined 203 as: 1) mild (non-pneumonia or mild pneumonia), 2) severe (dyspnea, respiratory rate 204 ≥30 breaths/min, percutaneous oxygen saturation ≤93% on room air at rest, arterial 205 oxygen tension over inspiratory oxygen fraction of less than 300 mmHg, and/or lung 206 infiltrates >50% within 24 to 48 hours, and 3) critical (severe respiratory distress, 207 respiratory failure requiring mechanical ventilation, shock, and/or multiple organ 208 dysfunction or failure). Normal laboratory reference ranges in each trimester of 209 pregnancy are in (43.5%, n=20) and third trimester (50.0%, n=23) pregnancies; only three cases were 235 detected in first trimester pregnancies (6.5%; Figure 1 ). Approximately two-thirds of 236 patients were either overweight (28.6%, n=12) or obese (35.7%, n=15) by their pre-237 pregnancy body mass index (BMI); two women met criteria for Class III Obesity (BMI 238 >40). Although the majority of patients were healthy, 26.1% (n=12) had an underlying 239 health condition(s) including type 2 diabetes (n=3), asthma (n=4), hypothyroidism (n=2), 240 hypertension (n=2), and several less common conditions (e.g. Crohn's treated with 241 immunosuppressive medication, seizure disorder history). Although no patients reported 242 smoking cigarettes during pregnancy, one reported marijuana use and one endorsed 243 alcohol use. 244 SARS-CoV-2 testing became increasingly available over the study period starting with 247 facility-based and outpatient "drive through" testing stations for symptomatic individuals 248 and expanding to universal screening on Labor & Delivery at several medical centers. 249

Nearly all pregnant patients (93.5%, n=43) were tested due to Covid-19-related 250 symptoms ( Table 2 ). The remaining three patients were asymptomatic but tested due to 251 known exposure. Women reported a median of two symptoms (IQR 1-5), which most 252 commonly included cough (69.8%, n=30), fever or chills (51.2%, n=22), nasal 253 congestion (48.8%, 21) and shortness of breath (44.2%, n=19; Table 2 ). Loss of taste or 254 smell was reported in 30.2% (n=13) of cases. Median time to symptom resolution was 255 24 days (IQR 13-37; Fig. 1 and Fig. S1 ). In one case, a woman with a prolonged 256 symptomatic course of at least 37 days, sought care in the emergency room three times 257

and was hospitalized once for respiratory symptoms. Follow-up data on symptoms were 258 not available for three women who were asymptomatic at SARS-CoV-2 testing. No co-259 infections were detected in seven patients (15.2%) tested for other respiratory viruses 260 (i.e. influenza and respiratory syncytial viruses). 261 262

The majority of cases were managed as outpatients for either mild in severity (78.3%, 264 36/46) or asymptomatic (6.5%, 3/46) presentations. Although few outpatients underwent 265 pulmonary imaging (12.8%, n=5/39), two women had pneumonia, but were not 266

admitted. An additional seven pregnant patients (15.2%) were hospitalized for Covid-19, 267 one of whom was admitted to the intensive care unit (Table 3) . Six of the seven 268 hospitalized patients met criteria for severe . Nearly all patients with severe disease were overweight or obese prior to pregnancy (80%, 4/5 with data) 270 and half had asthma and obesity-associated conditions (e.g. hypertension). Three 271 (42.9%) hospitalized patients received Covid-19-directed medications including 272 hydroxychloroquine and remdesivir (n=1) or remdesivir alone (n=2). Two patients 273 received azithromycin without concomitant hydroxychloroquine; one for possible 274 community acquired pneumonia and one in the setting of asthma exacerbation. 275

Laboratory testing was performed in 24 women, who were either hospitalized for Covid-277 19 (n=7) or managed as an outpatient (n=17); due to multiple encounters, including 278 delivery admission, laboratory test results were evaluated from the time of Covid-19 279 diagnosis until delivery (Table 3, Table S2 ). Of the 24 patients with white blood cell 280 measurements, eight had leukopenia (33%) using pregnancy-specific laboratory 281 reference ranges (<5.6 x 10 3 per µl; Table S1 ); half of these patients (4/8) were 282 managed as outpatients. Neither creatinine nor C-reactive protein was elevated in those 283 who had testing (creatinine, 0/21; C-reactive protein, 0/6; Table S1 ). Seven patients had 284 a mildly elevated aspartate aminotransferase (AST), including five managed as 285 outpatients (31.3%, 5/16) and two that were hospitalized (33.3%, 2/6). Lastly, a 286 markedly elevated D-dimer was detected in one of five patients (20%) in which the test 287 was ordered (Case 25: 4.08 ng/mL, Table 3 ). 288

The patient admitted to the intensive care unit was a young woman (20-25 years old) at 290 30 weeks, who presented with a one-week history of fever and cough. She was 291 overweight prior to pregnancy (BMI 26.2) and had asthma. She was admitted to the 292 intensive care unit due to acute respiratory failure with a percutaneous oxygen 293 saturation as low as 82% on room air and a respiratory rate as high as 49. She received 294 remdesivir (6 doses), hydroxychloroquine and high flow oxygen. She was transferred 295 out of the intensive care unit on day 3 and discharged home on day 6 ( 

During the study period, 8 (17.4%) patients delivered, including seven live births and 300 one stillbirth (Table 4 ). The median number of days between a positive SARS-CoV-2 301 test and delivery was 7.5 days (IQR 5.0-11.5). The median gestational age at delivery 302 was 38.4 weeks (IQR 37.5-39.8). In one case, worsening respiratory status and multiple 303 co-morbidities, including Class III obesity, led to the decision to deliver the patient 304 preterm at 33 weeks gestation (Case 27, Table 3 ). Of the eight deliveries, five (62.5%) 305 were vaginal and 3 (37.5%) were cesarean delivery. Two of the three cesarean 306 deliveries were performed, in part, to improve maternal respiratory status due to Covid-307 19 disease. During the delivery admission, two women developed postpartum 308 preeclampsia with severe features within one day of delivery; both women had elevated 309 blood pressure, but no pre-eclampsia-associated laboratory abnormalities. In these two 310 cases, intravenous anti-hypertensive medications were administered, but magnesium 311 sulfate was not given due to concern for exacerbating pulmonary edema. Pregnant patients with severe Covid-19 were nearly all overweight or obese prior to 327 pregnancy and many had additional co-morbidities including asthma and hypertension. 328

Obesity as a risk factor for severe Covid-19 in pregnancy is particularly concerning as 329 the national prevalence of obesity was 39.7% among women of reproductive age (20-330 39 years old) in 2017-2018(27) . Obesity is known to impair lung function through both 331 mechanical and inflammatory pathways(28). A synergistically detrimental impact on 332 maternal lung function may occur in the setting of multiple factors such as a Covid-19 333 pneumonia, obesity, asthma, and the added mechanical stress of an enlarged uterus in 334 late pregnancy; this combination may also increase the risk for a medically-indicated 335 preterm birth to improve maternal respiratory status. 336

Similar to the non-pregnant population, descriptions of the clinical course of Covid-19 339 disease in pregnancy have been variable (7, 17, 25) . A systematic review of early case 340 series was notable for a low rate of admission to the intensive care unit (3%), no 341 maternal deaths, and only one neonatal death and one intrauterine fetal demise(6). In a 342 recent and larger case series from the Hubei province in China, the rate of severe 343 pneumonia (7-8%) in pregnant women was not higher than the general population 344 (15%)(7). Newer reports have highlighted critical cases in pregnant women involving 345 respiratory failure, mechanical ventilation, maternal death, as well as obstetrical 346 complications like preterm birth and intrauterine fetal demise (8, 17, (29) (30) (31) (32) 

Rigorous population-based studies are needed to identify risk factors for severe 394 disease, the rate of adverse outcomes in pregnancy and to ascertain whether risks are 395 increased in late pregnancy similar to influenza(41-43). Whether vertical transmission 396 occurs remains unknown, but several case reports appear suspicious (16-18). We must 397 also conduct follow-up studies of children exposed to SARS-CoV-2 infections in 398 pregnancy to determine the risk for Covid-19 disease in the immediate newborn period. 399

Both preterm birth and maternal infections may pose short-and long-term risks for the 400 child including mortality, prematurity-related complications, and neuropsychiatric 401 disease as an adult (19, 20, 44, 45) . Finally, we must determine the impact of quarantine 402 and mother-newborn separation on maternal health so that we can better support 403 women in the postpartum period. 

Pregnant patients with severe Covid-19 disease were non-Hispanic white (n=4), Hispanic race unknown (n=1), and race/ethnicity unknown (n=1).

Abbreviations: AST: aspartate transaminase; ALT: alanine aminotransferase; CXR: Chest X-ray; GA: gestational age; CS: cesarean section; ICU:

intensive care unit; RR: respiratory rate; WBC: white blood cells * Age group (5 year increments) is presented to make it less likely that a patient might be identifiable. † Pre-pregnancy BMI not available. This value represents BMI at SARS-CoV-2 diagnosis, which was at 14 weeks gestation. ‡ This patient had three emergency department visits for respiratory concerns, one of which prompted this hospitalization. 

Days between positive test and delivery 7.5 (5.0-11.5) * Characteristics summarized as n(%) or median(IQR). † One patient with spontaneous onset of labor had labor subsequently augmented. ‡ Reasons for inductions included fetal demise n=1, premature rupture of membranes n=1, diabetes n=1, hypertensive disorders of pregnancy n=1, growth restrictions n=1, scheduled induction n=2. No inductions of labor were performed to improve maternal lung function. § Cesarean section indications included (multiple indications in some cases): repeat cesarean delivery n=2, non-reassuring fetal status=1, diabetes n=1, respiratory compromise n=1, second stage arrest n=1, malpresentation n=1, Covid-19 n=2 (decision in the context of Covid-19 and other co-morbidities n=1, worsening respiratory status n=1), other n=1 (cholestasis, history of shoulder dystocia, fetal macrosomia this pregnancy) ** Treated with insulin. † † Diagnosed concurrently with (n=1) or after positive SARS-CoV-2 test (n=1) ‡ ‡ Both cases were defined as severe by blood pressure criteria. for each patient, as applicable. Three patients were asymptomatic. Of the seven 608 patients hospitalized for Covid-19 associated respiratory concerns, six were severe 609 (Table 3) .

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We would like to acknowledge several individuals for their support of this project.